Pathologic (path) response (resp) is an excellent surrogate marker for long-term recurrence-free survival after neoadjuvant (neoadj) IPI + NIVO in stage III melanoma. Few resp pts develop recurrence of disease, and their clinical characteristics and mechanisms of tumor immune escape are unknown.
In the OpACIN, OpACIN-neo and PRADO trials, pts with recurrence after path resp were identified. All pts received 2x IPI + NIVO neoadj (different dosing regimens) and surgery at week 6. Path resp was classified as major path response (MPR; ≤10% vital tumor) or path partial response (pPR; >10-≤50% vital tumor). Multiplex immunofluorescence staining (CD3, CD8, CD20, CD68, FoxP3, Sox10, DAPI) of paired baseline and recurrent samples was performed. Tumor and stroma regions were classified and % staining-positive cells determined using HALO imaging software.
In the three trials, 142 pts obtained path resp, of whom 11 (8%) had a recurrence (n=6/118 [5%] of MPR pts and n=5/24 [21%] of pPR pts). Clinical characteristics were comparable for pts with and without recurrence, except for more frequent BRAF-mutations (73% vs 35%, p=0.044) and less frequent MPR (55% vs 85%, p=0.009) in pts with recurrence. Five pts had a regional recurrence (45%) and 6 pts distant metastases (55%), median 6.7mo and 13.1mo post surgery, respectively. Matched baseline and recurrence multiplex data were available for 6 pts (3 pts had regional and 3 pts distant recurrence): 4 MPR and 2 pPR pts. The percentage of CD3+, CD8+, FoxP3+ and CD68+ cells was increased at recurrence in both pPR patients, while in 3/4 MPR pts tumor immune infiltration was decreased at recurrence. Additional spatial analyses defining the nearest neighbor cell will be presented at ESMO.
Obtaining MPR is a surrogate marker for having an excellent clinical outcome. BRAF-mutation and response depth seem associated with recurrence after resp to neoadj IPI + NIVO in stage III melanoma. Regional recurrences were diagnosed earlier than distant metastases. Multiplex staining shows a trend of in- or decrease of immune cell populations according to initial depth of response, although the data presented is based on small numbers.
Clinical trial identification
Legal entity responsible for the study
Bristol Myers Squibb.
A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Role: Ipsen, Roche, Bristol Myers Squibb, Pfizer, MSD, Sanofi, Pierre Fabre, Novartis, Eisai, Merck. E. Kapiteijn: Financial Interests, Institutional, Advisory Board: BMS, Novartis, Pierre Fabre, Merck, Delcath, Bayer; Financial Interests, Institutional, Invited Speaker: BMS. W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen, BMS; Financial Interests, Institutional, Advisory Board: Belpharma; Financial Interests, Institutional, Expert Testimony: Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis. R.P.M. Saw: Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme, Qbiotics; Financial Interests, Personal, Advisory Role, Speaker's Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb. C.L. Zuur: Financial Interests, Institutional, Sponsor/Funding: BMS. B. van de Wiel: Financial Interests, Personal, Full or part-time Employment: BMS. R.A. Scolyer: Financial Interests, Personal, Advisory Role: F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharo & Dohme, NeraCare, Amgen, Bristol Myers Squibb, Myriad Genetics, GlaxoSmithKline. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers-Squibb, Novartis, MSD - Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Uniti Cars, co-founder Immagene BV; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, NanoString, 4SC. All other authors have declared no conflicts of interest.